Primary hepatocellular carcinoma (PHC) is the third most common cancer in China and the most common cancer in the coastal provinces of Guangxi, Guangdong, Fujian, Zhejian, Jiangsu, and Shanghai. Because the survival rate is so dismal (less than 5%), PHC is also the most common cause of cancer deaths in these areas. About 80% of the PHCs in these provinces (and all of China) are associated with chronic infection with hepatitis B virus (HBV), but the unequal distribution of PHC incidence rates within these high risk provinces correlates only weakly with the prevalences of chronic carriers of HBV. Other factors that act independently of, or synergistically with, HBV must be involved, but are poorly understood. The overall goal of this project is to identify, within the context of a 5 year prospective, nested case-control study of 46,350 men in Haimen County, Jiangsu Province, China, factors (in addition to HBV infection) that contribute to the high risk of PHC. About 255 cases of PHC are expected to occur in this population in 5 years. The method for accomplishing this goal is to test hypotheses of association of specific variables with risk of PHC, by collecting biological samples and exposure information by questionnaire, at the beginning of the study, and making laboratory measures of person-specific exposures in these biological samples from each PHC case and two controls at the time of occurrence of each case. The Specific Aims consist of testing the following variables as risk factors for PHC: a) Exposure to aflatoxin B1; b) Chronic infection with hepatitis C virus; c) Decreased body stores of selenium; d) Increased body iron stores; e) Tobacco use. The relationship of these variables to each other, to chronic HBV infection, and to PHC risk will be evaluated. Information on alcohol use, water source, dietary consumption of cruciferous vegetables, corn, rice, peanuts, and green tea will be obtained by questionnaire and related to risk of PHC and to interactions with the other variables. About 125,000 people die each year from PHC in China. Vaccination against HBV may eventually reduce this mortality by 80%, but that is unlikely to happen for several decades. In the meantime, understanding the various environmental and genetic factors that affect this risk could lead to relatively simple measures for reducing PHC mortality not only in China, but also in the United States and other developed countries.